An affibody-adalimumab hybrid blocks combined IL-6 and TNF-triggered serum amyloid A secretion in vivo

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Yu, FeifanKTH,Proteinteknologi (author)

An affibody-adalimumab hybrid blocks combined IL-6 and TNF-triggered serum amyloid A secretion in vivo

Article/chapterEnglish2014

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2014-11
Informa UK Limited,2014
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LIBRIS-ID:oai:DiVA.org:kth-159385
https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-159385URI
https://doi.org/10.4161/mabs.36089DOI
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-243059URI

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Language:English
Summary in:English

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QC 20150203
In inflammatory disease conditions, the regulation of the cytokine system is impaired, leading to tissue damages. Here, we used protein engineering to develop biologicals suitable for blocking a combination of inflammation driving cytokines by a single construct. From a set of interleukin (IL)-6-binding affibody molecules selected by phage display, five variants with a capability of blocking the interaction between complexes of soluble IL-6 receptor a (sIL-6R alpha) and IL6 and the co-receptor gp130 were identified. In cell assays designed to analyze any blocking capacity of the classical or the alternative (trans) signaling IL-6 pathways, one variant, Z(IL-6_13) with an affinity (K-D) for IL-6 of similar to 500 pM, showed the best performance. To construct fusion proteins ("AffiMabs") with dual cytokine specificities, Z(IL-6_13) was fused to either the N-or C-terminus of both the heavy and light chains of the anti-tumor necrosis factor (TNF) monoclonal antibody adalimumab (Humira (R)). One AffiMab construct with Z(IL-6_13) positioned at the N-terminus of the heavy chain, denoted Z(IL-6_13)-HCAda, was determined to be the most optimal, and it was subsequently evaluated in an acute Serum Amyloid A (SAA) model in mice. Administration of the AffiMab or adalimumab prior to challenge with a mix of IL-6 and TNF reduced the levels of serum SAA in a dose-dependent manner. Interestingly, the highest dose (70 mg/kg body weight) of adalimumab only resulted in a 50% reduction of SAA-levels, whereas the corresponding dose of the Z(IL-6_13)-HCAda AffiMab with combined IL-6/TNF specificity, resulted in SAA levels below the detection limit.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinsk bioteknologi hsv//swe
MEDICAL AND HEALTH SCIENCES Medical Biotechnology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Annan medicin och hälsovetenskap Övrig annan medicin och hälsovetenskap hsv//swe
MEDICAL AND HEALTH SCIENCES Other Medical and Health Sciences Other Medical and Health Sciences not elsewhere specified hsv//eng
AffiMab
Antibody
IL-6
TNF
adalimumab
affibody
affinity
fusion
inflammation

Added entries (persons, corporate bodies, meetings, titles ...)

Gudmundsdotter, Lindvi (author)
Akal, AnastassjaKTH,Proteinteknologi(Swepub:kth)u1xutmx7 (author)
Gunneriusson, Elin (author)
Frejd, FredrikUppsala universitet,Institutionen för radiologi, onkologi och strålningsvetenskap (author)
Nygren, Per-ÅkeKTH,Proteinteknologi(Swepub:kth)u1zhverl (author)
KTHProteinteknologi (creator_code:org_t)

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In:mAbs: Informa UK Limited6:6, s. 1598-16071942-08621942-0870

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By the author/editor: Yu, Feifan; Gudmundsdotter, ...; Akal, Anastassja; Gunneriusson, El ...; Frejd, Fredrik; Nygren, Per-Åke

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